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inhibitors in rodent pain models, one such compound failed in an

OA pain clinical trial – most likely because of the redundancy of

the endocannabinoid system.

On the basis of the unsatisfactory outcome of current OA

therapies, researchers from Krakow, under the supervision of Dr

Katarzyna Starowicz, tested the analgesic activity of OMDM-198, a

piperazinyl carbamate which inhibits FAAH with good potency and

also interacts with excitatory TRPV1 receptors in a chemically

induced animal model of OA. Systemic administration of a dual

FAAH/TRPV1 blocker can reduce joint pain. Indeed, throughout

the time course of this study, OMDM-198 exhibited a significant

reversal of joint hypersensitivity. The benefits of the two-way action

profile of the new compound’s hybrid compared to the

compounds acting to only one biological component (FAAH or

TRPV1) include better efficacy and a better safety profile than the

standard drug selective. The optimal doses required to achieve a

comparable analgesic effect were much higher for the single-

target drugs than for OMDM-198.

In summary, the model of intra-articular MIA injections provides a

preclinical tool in which consistent pain readouts are inhibited by

OMDM-198, a synthetic compound that inhibits FAAH and

antagonises TRPV1. Collaborative research conducted in the Pain

Pathophysiology Lab in Krakow may lead to an innovative

pharmacotherapy strategy for OA. The proposed study of the

interaction of two different systems that control endogenous

nociceptive neurotransmission is an alternative approach to

treating chronic pain and takes into account the dualistic nature

of the TRPV1 receptor ligands and CB

1

. Exploring the potential of

hybrid analgesic compounds interacting with these systems can

contribute to the creation of a new, effective and commonly used

therapy for chronic pain. Finding new molecular targets in OA

might result in the development of disease-modifying

osteoarthritic drugs.

Time to reconsider the definition of OA

A few decades ago, scientists were convinced that the clinical

state described as OA results mainly from cartilage breakdown

connected with mechanical expenditure. Recent experimental

data has shown that inflammatory processes may underlie

initiation and prolongation of OA, thereby opening the way to

considering inflammation as a crucial factor in the disease.

The classification of osteoarthritis as a non-inflammatory arthritis

is an unfortunate consequence of early observations noting fewer

leukocytes in OA synovial fluid compared with that of rheumatoid

arthritis, which is unarguably an inflammatory condition. Given its

role in numerous chronic diseases, chronic inflammation should

now be considered a key driver of progressive degeneration in OA

joints. Pain Pathophysiology Lab members believe that the

cytokine profile before OA initiation, at the initial stage of the

disease, as well as at a late stage, may differ substantially and

may correlate with OA pain severity. Scientists will focus their

research activities on different aspects of the inflammation in the

pathogenesis of OA. This may result in new information about

cytokine impact on the clinical situation.

Time to prevent: future directions

Most current research highlights the fact that all of the joint

components, particularly subchondral bone, undergo functional

and structural changes during OA progression. Given the intimate

contact between the cartilage and bone, alterations of either

tissue will modulate the properties and function of the other joint

component. Starowicz’s group address the strong need for novel

studies to define the pathophysiological mechanisms involved in

the interaction between subchondral bone and articular cartilage

and for applying this information to the development of

therapeutic interventions to improve the outcomes of patients

with OA.

The group will now focus on the molecular bone pathology in

order to support the concept that appropriate control of bone

remodelling may contribute to the maintenance of joint

functionality and stability. Beneficial effects resulting from a better

understanding of changes in subchondral bone and indication of

new molecular targets to develop effective treatment strategies

will help to direct treatment options to not only alleviate disease

consequences but also minimise the underlying OA causes. The

discovery of our future research may be a key to understanding

OA, its possible prevention, and its treatment.

Katarzyna Starowicz PhD

Associate Professor

Pain Pathophysiology Lab

Department of Pharmacology

Institute of Pharmacology

Polish Academy of Sciences

tel :

+48 12 6623206

starow@if-pan.krakow.pl http://www.painlab.pl/ www.horizon2020projects.com

H O R I Z O N 2 0 2 0 P R O J E C T S : P O R TA L

I S S U E S E V E N

131

P R O F I L E

S O C I E TA L C H A L L E N G E S : H E A L T H & W E L L B E I N G

Pain Pathophysiology Lab members. Standing, left to right: Natalia

Malek, Katarzyna Starowicz (Chair), Magdalena Kostrzewa, Mateusz

Kucharczyk, Agnieszka Pajak. Pain Lab was established in June 2013.

Research is supported by the National Science Centre, Poland by grant

SONATA BIS NCN/2012/07/E/NZ7/01269 and OPUS

NCN/2014/13/B/NZ7/02311